Validation Guide

Cadence™ Inline Concentrator with Delta and Omega™ Membranes

USTR 2911b

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Contents

1. Introduction................................................................................................................................................3

1.1 Purpose of this Document....................................................................................................................3

1.2 Validating a Filtration Process – General Concepts...............................................................................3

2 Cadence Inline Concentrator Modules ....................................................................................................4

2.1 Packaging ............................................................................................................................................4

2.2 Labeling and Product Identification.......................................................................................................4

2.3 Part Numbers.......................................................................................................................................6

2.4 Serial Numbers.....................................................................................................................................8

3 Materials of Construction .........................................................................................................................9

4 Integrity Testing .........................................................................................................................................9

4.1 Principles..............................................................................................................................................9

4.2 Specifications .......................................................................................................................................9

4.3 Obtaining Reliable and Reproducible Results .......................................................................................9

5 Shelf Life ..................................................................................................................................................10

6 Compatibility with Sanitizing Agent .......................................................................................................10

7 Operating Pressures and Temperatures ................................................................................................10

8 Extractables.............................................................................................................................................10

9 Biocompatibility Conformance ...............................................................................................................10

9.1 Summary............................................................................................................................................10

9.2 Materials of Construction Conformance .............................................................................................11

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1. Introduction

1.1 Purpose of this Document

This document provides validation support information for Cadence Inline Concentrator (ILC)modules with Centramate™ and Centrasette™ cassettes with Delta and Omega membranes.The document includes summary data from tests conducted for biological safety, extractables,chemical compatibility, physical and performance attributes, as well as usage conditions.

The data contained in this guide was generated under standard conditions as specified. Themethods and information contained in this guide are designed to provide the user with anacceptable approach for validation of Cadence ILC modules under actual conditions of use.

Using the information and methods in this validation guide, the end-user should be able toprepare procedures for actual use of the Cadence ILC modules which can be validated toensure consistent performance and to meet regulatory requirements.

If needed, Pall Biotech offers technical support to customers to develop, troubleshoot, andvalidate Cadence ILC module procedures.

1.2 Validating a Filtration Process—General Concepts

Tangential flow filtration (TFF) membrane cassettes play an essential role in purifying,concentrating, and separating biopharmaceutical solutions and products. For example,established TFF applications include concentrating human plasma fractions, downstreamprocessing of enzyme and protein solutions, and harvesting mammalian or bacterial cells. Toensure these TFF processes result in safe and efficacious products, the FDA requires validationof these processes.

The U.S. Food and Drug Administration defines validation as “…establishing documentedevidence which provides a high degree of assurance that a specific process will consistentlyproduce a product meeting its predetermined specification and quality attributes.” [CurrentGood Manufacturing Practice (cGMP) for Finished Pharmaceuticals, 21 CFR 210.3]. Withrespect to a TFF process, validation involves providing assurance that the filtration processoperates reproducibly and consistently.

The first step in Cadence ILC process validation is to create a functional design specification.Users base the functional design specification on the requirements of the TFF process and thedata generated during pilot scale runs. A functional design specification should includeoperational protocols. The operational protocols should be consistent with the performancelimits outlined in this Validation Guide and the Cadence ILC module User Guide (Pall documentreference USD 2841) found at www.pall.com/procedures.

The second step is to design and develop a Cadence ILC process that enables the directscale-up of the specifications established during pilot or bench-scale runs. Three stages ofprocess validation are typically followed: Installation Qualification (IQ), Operational Qualification(OQ), and Performance Qualification (PQ).

Installation Qualification (IQ)

An installation qualification verifies that the Cadence ILC module’s operating instructions andcertificate of conformance were received and that the installation of the Cadence ILC modulewas completed in accordance with the operating instructions.

Operational Qualification (OQ)

During an operational qualification, validation personnel test and document the range andoperational limits of the filtration process with a Cadence ILC module in place. An operationalqualification does not have to be conducted in a user’s manufacturing area.

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Validation personnel normally simulate worst-case production conditions for these operationalqualification studies, using water or another surrogate process fluid. The goal is to deliberatelytrigger alarm conditions. As part of the operational qualification, validation personnel also verifyand document procedures such as flushing and sanitizing that are associated with theoperation of the Cadence ILC module.

Performance Qualification (PQ)

Performance qualification involves testing the Cadence ILC process during production of thefinal product under actual operating conditions including: installation, sanitization, conditioning,concentration, product recovery and post-use sanitization (if necessary), etc. Critical elements ofa performance qualification include verifying chemical compatibility between the final productand the wetted components of the filtration system, and the retention characteristics of thefiltration system.

Data from a performance qualification is derived from the filtration process using the actualproduct and process conditions. Therefore, it provides the most meaningful process validationdata. PQ may not necessarily provide data on the operation of the module at the design limits(maximum pressure, etc.), as the process may never reach these limits.

Manufacturers of regulated products must develop and submit protocols, qualificationdocuments, and validation documents for their specific product to be granted approval tomanufacture and market their product.

2 Cadence Inline Concentrator Modules

2.1 Packaging

Cadence ILC modules are double bagged to protect the modules from damage andcontamination. Both the inner and outer clear plastic bags are heat sealed.

Each bagged Cadence ILC module is packed in boxes with protective foam inserts along with a Certificate of Quality. The care and use guide and safety data sheet can be found online at www.pall.com/procedures.

2.2 Labeling and Product Identification

Product labeling and individual serial numbers ensure definitive identification of Cadence ILCmodules and traceability of module components.

Product labels are included on the packaging box and on the plastic bag. Productionidentification information is also printed on the side of each module. The module serial number,included in all three locations, enables traceability of components.

The labels on the box and bag include the following information:

l Manufacturer’s namel Product namel Part numberl Serial numberl Quantityl Date of manufacture

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Figure 1Bag and box label for Cadence ILC modules

Each module includes the following information printed on it (Figure 2):

• Company name• Module membrane area• Part number• Serial number• www.pall.com/patents• Port names• Maximum operating pressure

Figure 2Information printed on each side of the Cadence ILC module

Example top and bottom plate laser marking for a Cadence ILC module with 30 kDa Delta membrane andT02 format cassette

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2.3 Part Numbers

A module’s part number identifies its purpose and design elements. For example, a CadenceILC module with Delta 10 kDa regenerated cellulose membrane in a T01 cassette format haspart number ILD010T010407.

IL Inline concentratorD or OS The module is made using cassettes with Delta (D) or Omega (OS) membrane 010 The NMWC of the membrane in kDaT01 T-series cassette format used in the module04 4-in-series flow path07 The total number of cassettes is 07

Part numbers and their associated modules are shown in Table 1.

Table 1Cadence ILC module characteristics and dimensions

Estimated DMinimum Total C Approx.Holding Module A B Width Width Port

Module Area Volume Weight Height Length (plate) (cap to cap) ConnectorPart Number (m2) (mL) kg (lbs) cm (in.) cm (in.) cm (in.) cm (in.) Type

ILD010T010407 0.065 20 2.1 (4.7) 9.8 (3.8) 27.4 (10.8) 9.3 (3.7) 20.7 (8.2) Female Luer

ILD030T010407

ILOS010T010407

ILOS030T010407

ILD010T020407 0.13 40 2.2 (4.9) 10.5 (4.1)

ILD030T020407

ILOS010T020407

ILOS030T020407

ILD010T120407 0.7 200 3.9 (8.5) 20.3 (8) 27.4 (10.8) 9.3 (3.7) 20.7 (8.2) Female MPC

ILD030T120407

ILOS010T120407

ILOS030T120407

ILD010T060407 3.5 1300 15.9 (35) 27.2 (10.7) 28.9 (11.4) 24.1 (9.5) 51.4 (20.2) Female MPX

ILD030T060407

ILOS010T060407

ILOS030T060407

See Figure 3 for dimension references

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Figure 3. Cadence ILC module dimensions for T01/T02, T06, and T12 cassette formats

T01 and T02 module configurations

T12 module configurationT06 module configuration

Cadence™ Inline Concentrator

Cadence™ Inline Concentrator

Cadence™ Inline Concentrator

D C

A

B

A

D C

B

D C

A

B

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2.4 Serial Numbers

The serial number on the package labels and printed on each Cadence ILC module enables the determination of the following:

• C = Cadence module

• Second digit is the last digit of the year of manufacture (e.g., for 2019, it is "9")

• Next three digits are the Julian date (e.g., 01-JAN is '001' and 01-FEB is '032')

• Next three digits are the cassette # or module # of the day, starting with 001

• Last digit R represents the facility where the product was assembled

Hence, if needed, Pall Biotech can trace the source of individual components used tomanufacture each module.

3 Materials of Construction

The materials of construction in the flow path of the Cadence ILC modules with T-series Centramateand Centrasette cassettes with Delta or Omega membrane are detailed in this section.

Materials of construction biosafety conformance summary is in Section 9.

• Membranes– Delta membranes are cast from cellulose resins on a polypropylene substrate.– Omega membranes are cast from polyethersulfone (PES) resins on a polyolefin substrate.

• ScreensThe screens used to separate the membrane layers in T-series cassettes are manufactured frompolypropylene.

• Support LayerThe Delta membrane in T-series cassettes contains an additional support layer manufactured frompolyolefin fiber.

• Cassette EncapsulantThe encapsulant used in T-series cassettes is polyurethane with a white pigment (TiO2).

• Permeate Seals, Gaskets, and TubingThe permeate seals, gaskets, and tubing are made from platinum-cured silicone rubber.

• Top and Bottom ManifoldsThe top and bottom manifolds in the Cadence ILC modules are constructed of high densitypolyethylene.

• ConnectorsThe connectors used in the Cadence ILC modules are made from polypropylene (Luer) andpolysulfone (MPC/MPX).

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4 Integrity Testing

4.1 Principles

The module integrity test measures the Forward Flow rates with air at specified pressures todetermine the integrity of membrane module. The air Forward Flow rate is a measure of airdiffusion through the liquid in the membrane pores, air flow through potential defects, plus airleakage around seals. The test identifies gross defects in the membrane or cassette seals.

During integrity testing, compressed air is applied to the feed port. The retentate port is closed,and both permeate ports are opened. Hence, the compressed air must flow through themembrane (and potential defects) and out of the open permeate ports.

4.2 Specifications

The integrity test specifications for the Cadence ILC modules are shown in Table 2.

Cadence ILC modules with Delta membrane are integrity tested at a test pressure of 4.1 barg(60 psig). The maximum air flow rate is 538 standard cubic centimeters per minute per squaremeter (sccm/m2) (50 sccm/ft2).

Cadence ILC modules with Omega membrane are integrity tested at test pressure of 2.1 barg(30 psig). The maximum air flow rate is 1600 sccm/m2 (150 sccm/ft2).

Nitrogen can be used in place of air.

Table 2Cadence ILC module integrity test parameters

Module Membrane Membrane Forward FlowPart Number Type Test Pressure Area (m2) Limit (sccm)

ILD010T010407 Delta, 10 kDa 4.1 barg (60 psig) 0.065 35

ILD010T020407 0.13 70

ILD010T120407 0.7 380

ILD010T060407 3.5 1900

ILD030T010407 Delta, 30 kDa 0.065 35

ILD030T020407 0.13 70

ILD030T120407 0.7 380

ILD030T060407 3.5 1900

ILOS010T010407 Omega, 10 kDa 2.1 barg (30 psig) 0.065 100

ILOS010T020407 0.13 210

ILOS010T120407 0.7 1100

ILOS010T060407 3.5 5600

ILOS030T010407 Omega, 30 kDa 0.065 100

ILOS030T020407 0.13 210

ILOS030T120407 0.7 1100

ILOS030T060407 3.5 5600

4.3 Obtaining Reliable and Reproducible Results

For best integrity test results, Pall Biotech recommends the use of dedicated integrity analyzersthat incorporate mass flow meters. When performing integrity testing, use only instrument-quality air or nitrogen from cylinders. Fluctuations in house air or nitrogen supplies, as well aschanges in temperature, can result in inconsistent measurements. Failing to fully wet-out themembrane in the Cadence ILC module prior to performing the membrane integrity testing canresult in high Forward Flow values.

5 Shelf Life

The recommended shelf life of new, unopened Cadence ILC modules stored in its respectivepreservative solution (5% ethanol + 1% sodium diacetate for modules with Delta membrane; 0.3 Nsodium hydroxide for modules with Omega membrane) is expected to be at least 1 year from the dateof manufacture.

To achieve satisfactory performance, it is recommended that the Cadence ILC modules be storedunopened in the original packaging, at ambient temperature 4-25 °C and protected from direct light.

Shelf life studies are ongoing. Users should test the membrane integrity prior to use. For further shelf life information, please contact your Pall Biotech representative.

6 Compatibility with Sanitizing Agent

Please see the User Guide for the Cadence Inline Concentrator (Care and Use Procedures), USD 2841for appropriate selection of compatible sanitizing agents.

7 Operating Pressures and Temperatures

Cadence ILC modules are intended to operate between 20 and 40 °C up to a feed pressure of 4.1 barg(60 psig). Note that devices can be operated at lower temperatures but this should be validated by theuser.

To demonstrate stability to these conditions and to simulate alternating processing and cleaning cycles,Pall Biotech tested Cadence ILC modules using recirculating deionized water. The modules weresubjected to five (5) 24-hour cycles at 20 °C at 4.1 barg (60 psig) with 4-hour hot cycles at 40 °C at 4.1 barg (60 psig) in-between.

In addition, Pall Biotech subjected Cadence ILC modules to an 8-hour cycle at 4 °C at 4.1 barg (60 psig) and an 8-hour cycle at 40 °C and 4.1 barg (60 psig).

Results

The modules remained integral throughout the temperature/pressure limit studies. Results show thatCadence ILC modules can operate at 20-40 °C at a feed pressure of 4.1 barg (60 psig). Devices can beoperated at lower temperatures, but this should be validated by the user.

8 Extractables

Please contact your Pall Biotech representative if you require information about extractablescharacterization of Cadence ILC modules with Delta or Omega membrane.

9 Biocompatibility Conformance

9.1 Summary

The materials of construction in the flow path in the Cadence ILC module were evaluated interms of biological safety. All materials met the requirements of USP <88> Biological ReactivityTest (in vivo) for Class VI-70 °C plastics, Biological Reactivity Test (in vitro) L929 MEM ElutionCytotoxicity, and Hemolysis Test. In addition, the fluid path components do not containmaterials of construction that are considered BSE or TSE risk materials according to currentlegislation and guidelines (reference European CPMP EMEA/410/01 and Code of FederalRegulations, Title 21 part 189.5).

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9.2 Materials of Construction Conformance

• Delta membrane and substrate — Meets USP <88> Biological Reactivity Test (in vivo) forClass VI-70 °C Plastics, USP <87> Biological Reactivity Test (in vitro) L929 MEM ElutionCytotoxicity, and Hemolysis Test. Membrane regenerated from cellulose resin that meets 21 CFR 175.300; 21 CFR 175.380; 21 CFR 175.390; 21 CFR 176.170; 21 CFR 177.1210;and 21 CFR 182.90. Polypropylene substrate meets 21 CFR 177.1520.

• Omega membrane and substrate — Meets USP <88> Biological Reactivity Test (in vivo) forClass VI-70 °C Plastics, USP <87> Biological Reactivity Test (in vitro) L929 MEM ElutionCytotoxicity, and Hemolysis Test. Membrane made from polyethersulfone (PES) that meets21 CFR 177.2440. Polyolefin substrate meets 21 CFR 177.1520.

• Plant-Origin Kosher Glycerin (used as humectant in membrane formulation, removed withflushing) — GRAS 21 CFR 182.1320. Also 21 CFR 175.105; 175.300; 175.320; 175.380;175.390; 176.179; 176.210; 177.1210; 177.2420; 178.3120; 182.90; 182.99.

• Polypropylene screens — Meets USP <88> Biological Reactivity Test (in vivo) for Class VI-70 °C Plastics, USP <87> Biological Reactivity Test (in vitro) L929 MEM ElutionCytotoxicity, Hemolysis Test, and 21 CFR 177.1520.

• Polyolefin fiber support layer — Meets USP <88> Biological Reactivity Test (in vivo) for Class VI-70 °C Plastics, USP <87> Biological Reactivity Test (in vitro) L929 MEM . Elution Cytotoxicity, Hemolysis Test, and 21 CFR 177.1520.

• Polyurethane encapsulant — Meets USP <88> Biological Reactivity Test (in vivo) for Class VI-70 °C Plastics, USP <87> Biological Reactivity Test (in vitro) L929 MEM ElutionCytotoxicity, and Hemolysis Test, and 21 CFR 175.105,300, 177.1680,2600.

• Polyethylene manifolds — Meets USP <88> Biological Reactivity Test (in vivo) for Class VI-70 °C Plastics, USP <87> Biological Reactivity Test (in vitro) L929 MEM ElutionCytotoxicity, Hemolysis Test, and 21 CFR 177.1520.

• Silicone gaskets — Meets USP <88> Biological Reactivity Test (in vivo) for Class VI-70 °CPlastics, USP <87> Biological Reactivity Test (in vitro) L929 MEM Elution Cytotoxicity,Hemolysis Test, and 21 CFR 177.2600.

• Silicone tubing— Meets USP <88> Biological Reactivity Test (in vivo) for Class VI-70 °CPlastics, USP <87> Biological Reactivity Test (in vitro) L929 MEM Elution Cytotoxicity,Hemolysis Test, and 21 CFR 177.2600.

• Silicone permeate seals — Meets USP <88> Biological Reactivity Test (in vivo) for Class VI-70 °C Plastics, USP <87> Biological Reactivity Test (in vitro) L929 MEM ElutionCytotoxicity, and Hemolysis Test.

• Polypropylene Luer connectors— Meets USP <88> Biological Reactivity Test (in vivo) forClass VI-70 °C Plastics, USP <87> Biological Reactivity Test (in vitro) L929 MEM ElutionCytotoxicity, Hemolysis Test, and 21 CFR 177.1520.

• Polysulfone Colder connectors— Meets USP <88> Biological Reactivity Test (in vivo) forClass VI-70 °C Plastics, ISO 10993-5 Biological Reactivity Test (in vitro) L929 MEM ElutionCytotoxicity, and Hemolysis Test.

Visit us on the Web at www.pall.com/biotechContact us at www.pall.com/contact

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The information provided in this literature was reviewed for accuracy at the time of publication. Product data may be subject to change without notice. For current information consult your local Pall distributor or contact Pall directly.

Corporate HeadquartersPort Washington, NY, USA+1 800 717 7255 toll free (USA)+1 516 484 5400 phone

European HeadquartersFribourg, Switzerland+41 (0)26 350 53 00 phone

Asia-Pacific HeadquartersSingapore+65 6389 6500 phone © 2018, Pall Corporation. Pall, , Allegro, Cadence, Centramate, Centrasette

and Omega are trademarks of Pall Corporation. Filtration.Separation.Solution is a service mark of Pall Corporation. ® indicates a trademark registered in the USAand ™ indicates a common law trademark.

11/18, PDF, GN18.10102 USTR 2911b